Hemi-methylated DNA regulates DNA methylation inheritance through allosteric activation of H3 ubiquitylation by UHRF1

Authors

Joseph S. Harrison, University of the PacificFollow
Evan M. Cornett, Van Andel Research Institute
Dennis Goldfarb, University of North Carolina at Chapel Hill
Paul A. DaRosa, University of Washington
Zimeng M. Li, University of North Carolina at Chapel Hill
Feng Yan, University of North Carolina at Chapel Hill
Bradley M. Dickson, Van Andel Research Institute
Angela H. Guo, University of North Carolina at Chapel Hill
Daniel V. Cantu, University of North Carolina at Chapel Hill
Lilia Kaustov, University of Toronto
Peter J. Brown, University of Toronto
Cheryl H. Arrowsmith, University of Toronto
Dorothy A. Erie, University of North Carolina at Chapel Hill
Michael B. Major, University of North Carolina at Chapel Hill
Rachel E. Klevit, University of Washington
Krzysztof Krajewski, University of North Carolina at Chapel Hill
Brian Kuhlman, University of North Carolina at Chapel Hill
Brian D. Strahl, University of North Carolina at Chapel Hill
Scott B. Rothbart, Van Andel Research Institute

ORCID

Joseph Harrison: 0000-0002-2118-6524

Document Type

Article

Publication Title

eLife

Department

Chemistry

ISSN

2050-084X

Volume

5

DOI

10.7554/eLife.17101

First Page

e17191

Publication Date

9-6-2016

Abstract

The epigenetic inheritance of DNA methylation requires UHRF1, a histone- and DNA-binding RING E3 ubiquitin ligase that recruits DNMT1 to sites of newly replicated DNA through ubiquitylation of histone H3. UHRF1 binds DNA with selectivity towards hemi-methylated CpGs (HeDNA); however, the contribution of HeDNA sensing to UHRF1 function remains elusive. Here, we reveal that the interaction of UHRF1 with HeDNA is required for DNA methylation but is dispensable for chromatin interaction, which is governed by reciprocal positive cooperativity between the UHRF1 histone- and DNA-binding domains. HeDNA recognition activates UHRF1 ubiquitylation towards multiple lysines on the H3 tail adjacent to the UHRF1 histone-binding site. Collectively, our studies are the first demonstrations of a DNA-protein interaction and an epigenetic modification directly regulating E3 ubiquitin ligase activity. They also define an orchestrated epigenetic control mechanism involving modifications both to histones and DNA that facilitate UHRF1 chromatin targeting, H3 ubiquitylation, and DNA methylation inheritance.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Harrison, J. S., Cornett, E. M., Goldfarb, D., DaRosa, P. A., Li, Z. M., Yan, F., Dickson, B. M., Guo, A. H., Cantu, D. V., Kaustov, L., Brown, P. J., Arrowsmith, C. H., Erie, D. A., Major, M. B., Klevit, R. E., Krajewski, K., Kuhlman, B., Strahl, B. D., & Rothbart, S. B. (2016). Hemi-methylated DNA regulates DNA methylation inheritance through allosteric activation of H3 ubiquitylation by UHRF1. eLife, 5, e17191. DOI: 10.7554/eLife.17101
https://scholarlycommons.pacific.edu/cop-facarticles/573